Gambogic Acid Inhibits Wnt/β-catenin Signaling and Induces ER Stress-Mediated Apoptosis in Human Cholangiocarcinoma

Document Type : Research Articles


1 Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.

2 Department of Basic Medical Science, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand.

3 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.

4 Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.

5 Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok, Thailand.

6 Excellent Center for Drug Discovery (ECDD), Mahidol University, Bangkok, Thailand.

7 Toxicology Graduate Program, Faculty of Science, Mahidol University, Bangkok, Thailand.

8 Center of Excellence on Environmental Health and Toxicology (EHT), Faculty of Science, Mahidol University, Bangkok, Thailand.


Objective: Gambogic acid (GA) has been reported to induce apoptosis in cholangiocarcinoma (CCA) cell lines. However, the molecular mechanisms underlying its anti-cancer activity remain poorly understood. This study was aimed to investigate GA’s effect on human CCA cell lines, KKU-M213 and HuCCA-1, and its associated mechanisms on Wnt/β-catenin signaling pathway. Methods: Cell viability, apoptosis, and cell cycle analysis were conducted by MTT and flow cytometry. The effect of GA mediated Wnt/β-catenin and ER stress were determined by luciferase-reporter assay, qRT-PCR, and western blot analysis. Results: GA exhibited potent cytotoxicity in CCA cells which was associated with significantly inhibited cell proliferation, promoted G1 arrest, and activated caspase 3 mediated-apoptosis. GA attenuated β-catenin transcriptional levels, decreased β-catenin protein, and suppressed the expression of c-Myc, a downstream target gene of Wnt/β-catenin signaling. GA activated genes involved in ER stress mechanism in KKU-M213 and enhanced CCA’s sensitivity to gemcitabine. Conclusion: Our findings reveal that the molecular mechanism underpinning anti-cancer effect of GA is partially mediated through the inhibition of Wnt/β-catenin signaling pathway and induction of ER stress induced-apoptosis. GA may serve as a promising therapeutic modality for amelioration of gemcitabine-induced toxicity in CCA


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